Respiratory 2003

Question 1

Answer (A)

Harrisons

Pulmonary Thromboembolism

Genetics

Rudolf Virchow postulated more than a century ago that three potentially overlapping factors predisposed to venous thrombosis: (1) local trauma to the vessel wall; (2) hypercoagulability; and (3) stasis. We now believe that many patients who suffer pulmonary thromboembolism (PTE) have an underlying inherited predisposition that remains clinically silent until an acquired stressor occurs such as surgery, obesity, or pregnancy (Table 261-1). When PTE is identified, a detailed family history for venous thromboembolism should be obtained.

Table 261-1: Stressors That May Precipitate Pulmonary Thromboembolism

Surgery, trauma
Obesity
Oral contraceptives, pregnancy, postpartum, postmenopausal hormone replacement
Cancer (sometimes occult) or cancer chemotherapy
Immobilization (stroke or intensive care unit patients)
Indwelling central venous catheter

Factor V Leiden

The most frequent inherited predisposition to hypercoagulability is resistance to the endogenous anticoagulant protein, activated protein C. The phenotype of activated protein C resistance is associated with a single point mutation, designated factor V Leiden, in the factor V gene. This missense mutation-a single nucleotide substitution of adenine for guanine 1691-causes an amino acid substitution of glutamine for arginine at position 506.

The prevalence of the heterozygous state was about 6% in healthy American male physicians participating in the Physicians' Health Study and was three times higher among those physicians who subsequently developed venous thrombosis. Furthermore, after anticoagulation (for at least 3 months) was completed and discontinued, those participants with factor V Leiden had a much higher rate of recurrent venous thrombosis than those without. A single-point mutation in the 3′ untranslated region of the prothrombin gene (G-to-A transition at nucleotide position 20210) appears to be associated with increased levels of prothrombin (factor II), the precursor of thrombin. In the Physicians' Health Study, the prevalence of the prothrombin gene mutation among control subjects was 3.9%. The G20210A mutation conferred an approximate doubling of the risk of venous thrombosis. Nevertheless, factor V Leiden is more common than all other (identified) inherited hypercoagulable states, including the prothrombin gene mutation, deficiencies in protein C, protein S, antithrombin III, and disorders of plasminogen (Chap. 117).

About half of patients with pelvic vein thrombosis or proximal leg deep venous thrombosis (DVT) have PTE, which is usually asymptomatic. Isolated calf vein or upper extremity venous thromboses also pose a risk (albeit lower) of PTE. Isolated calf vein thrombi are the most common source of paradoxical embolism.

Clinical Syndromes

Patients with massive PTE present with systemic arterial hypotension and usually have anatomically widespread thromboembolism. Primary therapy with thrombolysis or embolectomy offers the greatest chance of survival. Those with moderate to large PTE have right ventricular hypokinesis on echocardiography but normal systemic arterial pressure. Optimal management is controversial; such patients may benefit from primary therapy to prevent recurrent embolism. Patients with small to moderate PTE have both normal right heart function and normal systemic arterial pressure. They have a good prognosis with either adequate anticoagulation or an inferior vena caval filter. The presence of pulmonary infarction usually indicates a small PTE, but one that is exquisitely painful, because it lodges near the innervation of pleural nerves.

Nonthrombotic pulmonary embolism may be easily overlooked. Possible etiologies include fat embolism after blunt trauma and long bone fractures, tumor embolism, or air embolism. Intravenous drug users may inject themselves with a wide array of substances, such as hair, talc, or cotton. Amniotic fluid embolism occurs when fetal membranes leak or tear at the placental margin. The pulmonary edema seen in this syndrome is probably due primarily to alveolar capillary leakage.

Symptoms and Signs

Dyspnea is the most frequent symptom of PTE, and tachypnea is its most frequent sign. Whereas dyspnea, syncope, hypotension, or cyanosis indicate a massive PTE, pleuritic pain, cough, or hemoptysis often suggest a small embolism located distally near the pleura. On physical examination, young and previously healthy individuals may simply appear anxious but otherwise seem deceptively well, even with an anatomically large PTE. They need not have "classic" signs such as tachycardia, low-grade fever, neck vein distention, or an accentuated pulmonic component of the second heart sound. Sometimes, a paradoxical bradycardia occurs.

Nonimaging Diagnostic Modalities

These are generally safer, less expensive, but also less specific than diagnostic modalities that employ imaging.

Blood Tests

The quantitative plasma D-dimer enzyme-linked immunosorbent assay (ELISA) level is elevated (>500 ng/mL) in more than 90% of patients with PTE, reflecting plasmin's breakdown of fibrin and indicating endogenous (though clinically ineffective) thrombolysis. A qualitative latex agglutination D-dimer assay, which is more readily available and less expensive than an ELISA, can be obtained initially; if elevated, the ELISA will also be elevated. However, if the latex agglutination is normal, a D-dimer ELISA should be obtained, because the ELISA is much more sensitive than the latex agglutination D-dimer assay, which cannot be used to exclude PTE. The plasma D-dimer ELISA has a high negative predictive value and can be used to help exclude PTE. However, neither D-dimer assay is specific. Levels increase in patients with myocardial infarction, sepsis, or almost any systemic illness.

Data from the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) indicate that, contrary to classic teaching, arterial blood gases lack diagnostic utility for PTE. Among patients suspected of PTE, neither the room air arterial PO2 nor calculation of the alveolar-arterial oxygen gradient can reliably differentiate or triage patients who actually have PTE at angiography.

Electrocardiogram

Classic abnormalities include sinus tachycardia; new-onset atrial fibrillation or flutter; and an S wave in lead I, a Q wave in lead III, and an inverted T wave in lead III (Chap. 226). Often, the QRS axis is greater than 90°. T-wave inversion in leads V1 to V4 reflects right ventricular strain.

Noninvasive Imaging Modalities

Chest Roentgenography

A normal or near-normal chest x-ray in a dyspneic patient suggests PTE. Well-established abnormalities include focal oligemia (Westermark's sign), a peripheral wedged-shaped density above the diaphragm (Hampton's hump), or an enlarged right descending pulmonary artery (Palla's sign).

Venous Ultrasonography

Confirmed DVT is usually an adequate surrogate for PTE. Ultrasonography of the deep venous system relies upon loss of vein compressibility as the primary criterion for DVT. About one-third of patients with PTE have no imaging evidence of DVT. In these situations, the clot may have already embolized to the lung or is in the pelvic veins, where ultrasonography is usually inadequate. Therefore, the workup for PTE should continue if there is high clinical suspicion, despite a normal ultrasound examination.

Lung Scanning (See also Chap. 251)

Lung scanning is the principal imaging test for the diagnosis of PTE. Small particulate aggregates of albumin labeled with a gamma-emitting radionuclide are injected intravenously and are trapped in the pulmonary capillary bed. A perfusion scan defect indicates absent or decreased blood flow, possibly due to PTE. Ventilation scans, obtained with radiolabeled inhaled gases such as xenon or krypton, improve the specificity of the perfusion scan. Abnormal ventilation scans indicate abnormal nonventilated lung, thereby providing possible explanations for perfusion defects other than acute PTE. A high probability scan for PTE is defined as having two or more segmental perfusion defects in the presence of normal ventilation ( Fig. 261-1).

Lung scanning is particularly useful if the results are normal or near-normal, or if there is a high probability for PTE. The diagnosis of PTE is very unlikely in patients with normal and near-normal scans but, in contrast, is about 90% certain in patients with high-probability scans. Unfortunately, fewer than half of patients with angiographically confirmed PTE have a high-probability scan. Importantly, as many as 40% of patients with high clinical suspicion for PTE and "low-probability" scans do, in fact, have PTE at angiography.

Chest CT

Computed tomography (CT) of the chest with intravenous contrast effectively diagnoses large, central PTE but may fail to detect more peripherally located thrombi that are clinically important. In a comparison with standard contrast pulmonary angiography at Massachusetts General Hospital, the sensitivity of chest CT for PTE was only 60%.

Echocardiography

This technique is useful for rapid triage of acutely ill patients who may have PTE. Bedside echocardiography can usually reliably differentiate among illnesses that have radically different treatment, including acute myocardial infarction, pericardial tamponade, dissection of the aorta, and PTE complicated by right heart failure. Detection of right ventricular dysfunction due to PTE helps to stratify the risk, delineate the prognosis, and plan optimal management.

Invasive Diagnostic Modalities

Pulmonary Angiography

Selective pulmonary angiography is the most specific examination available for establishing the definitive diagnosis of PTE and can detect emboli as small as 1 to 2 mm. A definitive diagnosis of PTE depends upon visualization of an intraluminal filling defect in more than one projection. Secondary signs of PTE include abrupt occlusion ("cut-off") of vessels; segmental oligemia or avascularity; a prolonged arterial phase with slow filling; or tortuous, tapering peripheral vessels.

Pulmonary angiography can be carried out safely among properly selected patients at hospitals that perform at least several studies per month. In PIOPED, the procedure resulted in death in five patients (0.5%), two of whom had severe heart failure prior to the procedure. Angiography is most useful when the clinical likelihood of PTE differs substantially from the lung scan result or when the lung scan is of intermediate probability for PTE.

Contrast Phlebography

This technique has been mostly replaced by ultrasonography. Venography is costly, uncomfortable, and occasionally results in contrast allergy or contrast-induced phlebitis. Contrast phlebography is worthwhile when there is a discrepancy between the clinical suspicion and the ultrasound result. Phlebography is also useful for diagnosing isolated calf vein thrombosis or recurrent DVT. A recently approved nuclear medicine test utilizing a synthetic peptide that binds preferentially to the glycoprotein IIb/IIIa receptors on activated platelets may eventually replace contrast phlebography in clinical practice. This radiopharmaceutical permits scintigraphic imaging of acute DVT and may be especially useful for differentiating acute from chronic DVT.

Integrated Diagnostic Approach

We advocate an integrated diagnostic approach to streamline the workup of PTE (Fig. 261-2). This strategy combines the clinical likelihood of PTE with the results of noninvasive testing especially D-dimer ELISA, venous ultrasonography, and lung scanning to determine whether pulmonary angiography is warranted.

Figure 261-2: PTE diagnosis strategy: An integrated diagnostic approach. U/S, ultrasound; PAgram, pulmonary arteriogram.

Treatment

Consensus guidelines from the American College of Chest Physicians are summarized as follows (see Table 261-4).

Table 261-4: Guidelines for the Treatment of Pulmonary Embolism

1.  Treat DVT or PTE with therapeutic levels of unfractionated intravenous heparin, adjusted subcutaneous heparin, or low-molecular-weight heparin for at least 5 days and overlap with oral anticoagulation for at least 4 to 5 days. Consider a longer course of heparin for massive PTE or severe iliofemoral DVT.
2.  For most patients, heparin and oral anticoagulation can be started together and heparin discontinued on day 5 or 6 if the INR has been therapeutic for two consecutive days.
· Continue oral anticoagulant therapy for at least 3 months with a target INR of 2.5 (range 2.0 to 3.0).
· Patients with reversible or time-limited risk factors can be treated for 3 to 6 months. Patients with a first episode of idiopathic DVT should be treated for at least 6 months. Patients with recurrent venous thrombosis or a continuing risk factor such as cancer, inhibitor deficiency states, or antiphospholipid antibody syndrome should be treated indefinitely.
· Isolated calf vein DVT should be treated with anticoagulation for at least 3 months.
· The use of thrombolytic agents continues to be highly individualized, and clinicians should have some latitude in using these agents. Patients with hemodynamically unstable PTE or massive iliofemoral thrombosis are the best candidates.
· Inferior vena caval filter placement is recommended when there is a contraindication to or failure of anticoagulation, for chronic recurrent embolism with pulmonary hypertension, and with concurrent performance of surgical pulmonary embolectomy or pulmonary endarterectomy.
/
*
Modified from TM Hyers et al: Antithrombotic therapy for venous thromboembolic disease Chest 114:561S, 1998.

Figure 261-3: Acute PTE management: Risk stratification. RV, right ventricular; IVC, inferior vena cava.

Heparin

Heparin binds to and accelerates the activity of antithrombin III, an enzyme that inhibits the coagulation factors thrombin (factor IIa), Xa, IXa, XIa, and XIIa. Heparin thus prevents additional thrombus formation and permits endogenous fibrinolytic mechanisms to lyse clot that has already formed. After 5 to 7 days of heparin, residual thrombus begins to stabilize in the endothelium of the vein or pulmonary artery. However, heparin does not directly dissolve thrombus that already exists.

Low-Molecular-Weight Heparins

These fragments of unfractionated heparin exhibit less binding to plasma proteins and endothelial cells and consequently have greater bioavailability, a more predictable dose response, and a longer half-life than unfractionated heparin. No laboratory monitoring or dose adjustment is needed unless the patient is markedly obese or has renal insufficiency. Therefore, low-molecular-weight heparins are far more convenient to use than unfractionated heparin.

A meta-analysis of more than 3,500 acute DVT patients showed that those treated with low-molecular-weight heparin had an overall 29% reduction in mortality and major bleeding compared with the unfractionated heparin group. Enoxaparin, originally approved for prophylaxis, has recently received Food and Drug Administration approval for treatment of PTE in the presence of DVT with a once-daily dose of 1.5 mg/kg subcutaneously. However, it is almost always administered as 1 mg/kg twice daily. Dalteparin is approved for prophylaxis but not for treatment of venous thromboembolism.

Warfarin

This vitamin K antagonist prevents carboxylation activation of coagulation factors II, VII, IX, and X. The full effect of warfarin often requires 5 days, even if the prothrombin time, used for monitoring, becomes elevated more rapidly. When warfarin is initiated during an active thrombotic state, the levels of protein C and S decline, thus creating a thrombogenic potential. By overlapping heparin and warfarin for 5 days, the procoagulant effect of unopposed warfarin can be counteracted. Thus, heparin acts as a "bridge" until the full anticoagulant effect of warfarin is obtained.